ABSTRACT Age-related changes in hormone levels occur in both men and women but are more pronounced in women approaching menopause, typically between the ages of 45 to 52 years old 1. Despite prior data addressing brain-aging differences in women and men, how hormone changes in midlife affect brain structure and cognition in women remains unclear. Women appear to be more vulnerable to cognitive decline during this peri-menopausal period 2, and there is general agreement that women experience memory deficits during this timeframe 3?6. Estrogen-depletion is widely regarded as a likely cause of cognitive impairment in peri-menopausal women 7 but the mechanistic understanding of how declining estrogen rates affect cognitive decline and brain changes is relatively poorly understood. In animal models, estrogen receptors are found throughout the brain, but predominate in limbic-related areas that play a crucial role in cognitive function 8. Specifically, these animal studies show hippocampal subfields Cornu Ammonis 1, 2, and 3 as densely populated regions of estrogen-receptors; activation of these estrogen-receptors has been shown to mediate estrogen's beneficial effect on synaptic plasticity as well as play a role in preventing neurodegeneration in hippocampal neurons 9,10. We propose here investigating the impact of declining estrogen levels on hippocampal structure and function in peri-menopausal women as part of our collaboration with the Human Connectome Project- Aging (HCP-A). This project makes use of the rigorously structured data collection pipeline HCP-A is using to objectively stage menopause data points. Although the data detailed here are being collected as part of the HCP-A project, with 103 subjects currently available and an additional 107 anticipated to be recruited over the coming 2 years, no support for subsequent investigations is included as part of the HCP-A; investigations proposing to answer scientific questions using the dataset must be funded with separate research support. Specifically, we will analyze high-field magnetic resonance imaging (MRI) data of the hippocampus in order to assess memory structures and function in fine detail and determine whether lower estrogen levels predict poorer memory performance in peri-menopausal women. We will also investigate whether hormone replacement therapy has a beneficial effect at mediating the effect of changes in estrogen levels in midlife women. We expect results from this project to shed light on the complex relationship between changes in hormone levels and subsequent effects on hippocampal structure and memory function in midlife.